Waade Ragnhild Birkeland, Christensen Hege, Rudberg Ida, Refsum Helge, Hermann Monica
Department of Psychopharmacology, Diakonhjemmet Hospital, School of Pharmacy, University of Oslo, Vinderen, Oslo, Norway.
Ther Drug Monit. 2009 Apr;31(2):233-8. doi: 10.1097/FTD.0b013e3181956726.
Aripiprazole, a relatively new antipsychotic drug, is metabolized by cytochrome P450 3A4 (CYP3A4) and CYP2D6 to an active metabolite, dehydroaripiprazole. As studies on pharmacokinetic drug interactions with aripiprazole are so far limited, the aim of the present study was to investigate the impact of comedication on serum concentrations of aripiprazole and dehydroaripiprazole in psychiatric patients in a clinical setting. A therapeutic drug monitoring database was screened for patients receiving aripiprazole tablets as part of their treatment. Of the 361 samples included, 78% were from patients receiving comedication. The remaining 79 samples constituted the control group. Steady-state dose-adjusted serum concentrations (concentration to dose ratios, C:D ratios) of aripiprazole, dehydroaripiprazole and the sum of aripiprazole and dehydroaripiprazole, and the metabolic ratio (dehydroaripiprazole/aripiprazole) in the different comedication groups were compared with controls. Coadministration of a CYP3A4 inducer resulted in approximately 60% lower mean C:D ratios of aripiprazole, dehydroaripiprazole, and the sum of aripiprazole and dehydroaripiprazole (P < 0.05, P < 0.01, and P < 0.01, respectively). Combination with a CYP2D6 inhibitor resulted in a 45% higher mean C:D ratio of aripiprazole (P < 0.05), with no effect on the C:D ratio of dehydroaripiprazole. When aripiprazole was coadministered with alimemazine or lithium, a 56% (P < 0.01) and 43% (P = 0.05) higher mean C:D ratio of aripiprazole, respectively, was observed. Olanzapine, risperidone injections, escitalopram, or lamotrigine also had statistically significant effects on aripiprazole disposition but to a lesser extent. In conclusion, concurrent treatment with CYP3A4 inducers, CYP2D6 inhibitors, alimemazine, or lithium resulted in changes in the systemic exposure of aripiprazole between 40% and 60%. This is of such a magnitude that dose adjustments of aripiprazole may be required.
阿立哌唑是一种相对较新的抗精神病药物，经细胞色素P450 3A4（CYP3A4）和CYP2D6代谢为活性代谢物去氢阿立哌唑。由于目前关于阿立哌唑的药代动力学药物相互作用的研究有限，本研究的目的是在临床环境中调查合并用药对精神病患者血清中阿立哌唑和去氢阿立哌唑浓度的影响。对一个治疗药物监测数据库进行筛选，以找出接受阿立哌唑片作为治疗一部分的患者。在纳入的361个样本中，78%来自接受合并用药的患者。其余79个样本构成对照组。将不同合并用药组中阿立哌唑、去氢阿立哌唑以及阿立哌唑和去氢阿立哌唑之和的稳态剂量调整血清浓度（浓度与剂量比，C:D比）以及代谢比（去氢阿立哌唑/阿立哌唑）与对照组进行比较。与CYP3A4诱导剂合用导致阿立哌唑、去氢阿立哌唑以及阿立哌唑和去氢阿立哌唑之和的平均C:D比分别降低约60%（P<0.05、P<0.01和P<0.01）。与CYP2D6抑制剂合用导致阿立哌唑的平均C:D比升高45%（P<0.05），而去氢阿立哌唑的C:D比无变化。当阿立哌唑与阿利马嗪或锂合用时，分别观察到阿立哌唑的平均C:D比升高56%（P<0.01）和43%（P = 0.05）。奥氮平、利培酮注射剂、艾司西酞普兰或拉莫三嗪对阿立哌唑的处置也有统计学上的显著影响，但程度较小。总之，与CYP3A4诱导剂、CYP2D6抑制剂、阿利马嗪或锂同时治疗导致阿立哌唑的全身暴露量变化在40%至60%之间。这种变化幅度可能需要调整阿立哌唑的剂量。
